1,2,4-Triazole antimycotic compositions and use thereof

ABSTRACT

Antimycotic compositions are produced which comprise an antimycotically effective amount of a 1,2,4-triazole of the formula:   OR A PHARMACEUTICALLY ACCEPTABLE NON-TOXIC SALT THEREOF WHEREIN X 1 is hydrogen or alkyl; X2 is hydrogen or alkyl; R1 is alkyl, unsubstituted or substituted aryl or unsubstituted or substituted aralkyl; R2 is hydrogen, alkyl or unsubstituted or substituted aryl; R3 is alkyl, cycloalkyl, unsubstituted or substituted aryl or unsubstituted or substituted aralkyl; and Y is a keto group or a functional derivative of a keto group, in combination with a pharmaceutically acceptable non-toxic, inert diluent or carrier.

ban-mu 70R 3389654: F

United States Patent m1 m1 3,890,44; Melser et al. June 17, 197

[541 1,2,4-TRIAZOLE Ammco'nc prise an sntimyooticslly effective amountor a 1,2,

COMPOSITIONS AND USE THEREOF trissole of the formula: [75] Inventors:Weener Meiser, v

- Wuppertal-Elberfeld; Woltm 2 Krlmer, Wuppertal- Barmen; Ksrl x HeinzBiicltel; Manfred Plempel, I both of Wuppertal-Elberfeld,'all of LGermany x1 T1 [73] Assignee: Bayer Alttlengesellschstt,Gennany 1 3 221Filed: Sept. 11,1973 R f g [2l] Appl. No.2 396,202 5-- [30] Appik'um ora pharmaceutically acceptable non-toxic sa Sept. 26, 1972 Germany; "it.n 2247186 thcnof wherein X "is hydrogen or slkyl; 52 us c 424/269;424/269 hydmmo, my]; [5 1 Int. Cl. es Alk 27/00 R! i flky];unjubgfigutgd or gubsfltutgfd ary] [58] Field of Search 424/269umubnimted or mtmimted m R' is hydrogen. 'slltyl or unsubstituted orsubstitute [56] Reterences'Cited w i 4.

I UNITED STATES PATENTS R is alkyl, 'cycloalky l, unsubstituted orsubstitute 3. 31373 3 1972 a .1 424 259 sryl or unsubstituted orsubstituted aralkyl; and 3.723.622 3/1973 Buchel eta]. 424/269 'Y is sketo'gtoup ors functional derivative of 3,755,349 3/1973 Timmler et sl.424/269 keto-H- group. in combination ,,with

pharmaceutically acceptable non-toxic, ine Primary Examiner-Stanley J.Friedman diluent or carrier.

[ ABSTRACT 38 Clslms, No Drawings Antimycotic compositions "are producedwhich coml 1,2,4-TRIAZOLE ANTIMYCOTIC COMPOSITIONS AND USE THEREOFantimy'cotically effective amount of a l, 2,4-triazlole as hereinbelowdefined, ora pharmaceutically acceptable non-toxic salt thereof incombination witha pharmaceutically acceptable non-toxic inert diluent orcarrier,

as well as' to the treatment of mycoses inhumans and animals byadministering an antimycotically effective amount of a 1,2,4-triazole ashereinbelow defined.

It has been suggested in the art that 1,2,4-triazoles are effectiveagainst fungi pathogenic to plants.

We have now made the surprising discovery that 1,2,4-triazoles of theformula:

l i N" l RIO-C-Y-R? R is alkyl, preferably of l to 6carbon atoms, and especially l to 4 carbon atoms, aryLpreferably of 6 to 10 carbon atoms',either unsubstituted orsubstituted by one or moresubstituentsrprcferably one to live substituents orparticularly one'tothreesubstituents or one or two substituents, which substituents may bethe same or different and are selected from the group-consistingofalkyl'ofl to Acarbon atoms, halogen especially fluorine,'-chlo ri ner-bromine, haloalkyl, preferably offlio'ncarbon atoms and of. 2 tohalogen atoms, especially fluorine and/or chlorine, alkoity,preferablyrofl'l or2 carbon' atoms and of 2 toVSqhaIog'e'ri atom s,particularly. fluorine and/or chlorine, nitro,'amino, phenylchlorophenyl particularly; fo chlorophenyh or; chlorophenyl, or. ar'alkyl, preferably; of'o to] towbon atoms in the, aryl'pOrti n and 'gl]"or 2, car bon atoms in the alkyl I portion eithergunsubstituted orsubstituted by one or more substituents, preferably one to fivesubstituentsor particularly one to three substituents or one ortwo-substituents,'w hich substituents may be the sameordifierentand areselected from the group consistingof. alkyl'ofl to 4 carbon atoms,halogen especially fluorine, chlorine or bromine, haloalkyl, preferablyoflt'o 2 carbon atoms and of 2 to 5 halogen'atoms',,especiallyfluorineand/or chlorine,- alkoxy, preferably of "l or 2 carbon atoms,haloalkoxy, preferably of l or 2 carbon atoms and of 2 m5 halogen atoms,particularly 7 finedg to said hu a oranimal.

2 fluorine and/or chlorine. nitro. phenyl, chloro phenyl particularlyo-chlorophenyl or p chlorophenyl, or amino; 8' is hydrogen, alkyl,preferably of l to 6 carbon 5 atoms, especially of l to 4 carbon atoms,or aryl preferably or 6 to 10 carbon atoms, either unsubsti tuted orsubstituted by one or more substituents preferably 1 to 5 substituentsor particularly 1 to 1 substituents or I or 2 substituents, whichsubstitu 10 cuts may be the same or different and are selecte from thegroup consisting of alkyl of l to 4 carboi atoms, halogen especiallyfluorine, chlorine or bro mine, haloalkyl, preferably of l or 2 carbonatom and of 2 to 6 halogen atoms, especially fluorint 5 and/or chlorine,alkoxy, preferably of l or 2 carbor atoms, haloalltoxy, preferably of lor 2 carbor atoms and of 2 to 5 halogen atoms, particularly flu orineand/or chlorine, nitro, amino, phenyl, chloro phenyl particularlyo-chlorophenyl or p chlorophenyl,

R is alkyl, preferably of l to 6 carbon atoms, espe clally of l to 4carbon atoms, cycloalkyl, preferabl of 3 to 7 carbon atoms andespecially 3, 5 or 6 car bon atoms, aryl, preferably of 6 to 10 carbolatoms, either unsubstitued or substituted by one o more substituents,preferably one to five substitu ents'or particularly one to threesubstituents or on or two substituents, which"substituents may be thtsame or different and are selected from the grow consisting of alkyl ofl to 4 carbon atoms, halogei especially fluorine, chlorine or bromine,haloalkyl preferably of l or 2 carbon atoms and of 2 to 5 ha] ogenatoms, especially fluorine and/or chlorine alkoxy, preferably of l or 2carbon atoms, haloalk 'ox'y, preferably of l or 2 carbon atoms and of 2It 5 halogen atoms, particularly fluorine and/or chlo rine, nitro,amino,- phenyl, chlorophenyl particu larly o-chlorophenyl orp-chlorophenyl, or aralky preferably of 6 to 10 carbon atoms in the arylpor 'tion and l or 2 carbon atoms in the alkyl portioi eitherunsubstituted or substituted by one or mor substituents, preferably oneto five substituents o particularly one to three substituents or one ortwl substituents, which substituents maybe the same 0 different and areselected from the group consist 'ing of alkyl of l to 4 carbon atoms,halogen espe cially fluorine, chlorine or bromine, haloalkyi preferablyof l to 2 carbon atoms. and of 2 to halogen atoms, especially flourineand/or chlorine allgoxy, preferably of for 2 carbon atoms, haloalk 'foayipreferably' of l or 2 carbon atoms and of 2 tr IS halogenatoms,'particularly fluorine and/or chlo rine, nits-o," phenyl,-chlorophenyl particularly 0 chlorophenyl orp-chlorophenyl or amino; andY is a lteto group or a functional derivative of a ket group, incombination with a pharmaceutically ac ceptable non-toxic,"iner'tdiluent or carrier. The antirn'ycotic compositions of the present invention showfa broad spectrum of activity against fun; pathogenic to humansand animals. The l,2,4-triazole and phannaceutically acceptablenon-toxic salt thereof as defined above are useful in treating mycoseinvhurna'ns andanimals by administering an'antirnycot cally effectiveamount of a 1,2,4-triazole as above dc w: :isLThe'present'inVention alsoincludes pharmaceuticz compositions in dosage unit form.

Alkyl as used above is intended to include branched alkyl moieties aswell as straight chain alkyl moieties.

According to one embodiment of the present invention X and X arehydrogen or methyl, ethyl, n-propoyl or isopropyl, preferably hydrogenor methyl and especially hydrogen. a

When R, R and R are alkyl moieties, they are preferably methyl, ethyl,n-propyl, i-propyl, n-butyl, i-butyl or t-butyl.

when R, R and R are aryl or aralkyl moieties, they are preferablyphenyl, naphthyl or benzyl unsubstituted or substituted by preferably lto 3 or especially 1 or 2 of the same or different substituents selectedfrom the group consisting of methyl, ethyl, n-propyl, l-propyl, n-butyl,i-butyl, t-butyl, halogen especially fluorine,

chlorine or bromine, haloalkyl of l or 2 carbon atoms and 2 to 5 halogenatoms, especially fluorine and/or chlorine, and particularly thetrifluoromethyl moiety, alkoxy of 1 or 2 carbon atoms, haloalkoxy of lor 2 carbon atoms and 2 to 5 halogen atoms particularly fluorine and/orchlorine and particularly fluoromethoxy, difluorochloromethoxy andtrifluoroethoxy, nitro, phenyl, o-chlorophenyl,' p-chlorophenyl andamino.

when R is a cycloalkyl moiety, it is preferably cyclm propyl,cyclopentyl or cyclohexyl.

The preferred functional derivatives of "the keto group Y are theketo-hydrate group, acetal groups derived from alkyl alcohols of l to 4carbon atoms, preferably methanol and ethanol, oximes or semicarbazonesof the keto group.

According to another embodiment of the present invention,

X is hydrogen or alkyl of l to 3 carbon atoms;

X is hydrogen or alkyl of l to 3 carbon atoms;

R is alkyl of 1 to 6 carbon atoms, aryl of 6 to 10 carbon atomsunsubstituted or substituted by one to five substituents selected fromthe group I consisting of alkyl of l to .4' carbon atoms, the same ordifferent halogen the same or differ ent haloalkyl of 1 or 2 carbonatoms and 2 to 5 halogen atoms, alkoxy of l' or 2 carbon atoms, the sameor different haloalkoxy of l or 2 carbon atoms and 2 to 5 halogen atoms,and nitro and amino or aryl substituted by phenyl or halophenyl, oraralkyl of 6 to lO'carbon atoms in the aryl moiety and! to 2 carbonatoms in the alkyl moiety unsubstituted or substituted by one to fivesubstituentsselected from the 'group consisting of alkyl of l to 4carbon atoms, the same or different halogen, the same or differenthaloalkyl of l or 2 carbon atoms and 2;.to 5' halogen atoms, alkoxy of lor 2 carbon'atoms, the same or different haloalkoxy of l or 2ca'rbonatoms and 2 to 5 halogen atoms, nitro and'amino' or aryl substituted byphenyl and halophenyl;

R is hydro'gen,.-alkyl of l --to 6 carbon atoms oraryl of 6 to 10 carbonatoms. unsubstitutedor substituted by oneto fivesubstituentsselectedffrom the group consisting of alkyl of 1 to 4 carbonatoms, the same of different halogen, the same'or different haloalkyl ofl or 2 carbon atoms and 2 to 5 halogen atoms, alkoxy ofl or 2 carbonatoms, the same or different haloalkoxy of l or 2 carbon atoms and 2 to5 halogen atoms, nitro and amino or aryl substituted by phenyl andhalophenyl;

R is alkyl of l to 6 carbon atoms, cycloalltyl of 3 to 7 carbon atoms,aryl of 6 to '10 carbon atoms unsubstituted or substituted by one tofive substituents selected from the group consisting of alkyl of l to 4carbon atoms, the same or different halogen, the same or differenthaloallryl of l or 2 carbon atoms and 2 to S halogen atoms, alltoxy of lor 2 carbon atoms, the same or different haloalkoxy of I or 2 carbonatoms and 2 to 5 halogen atoms, nitro and amino or aryl substituted byphenyl and halophenyl or aralkyl of 6 to 10 carbon atoms in the arylmoiety and l or 2 carbon atoms in the alkyl moiety unsubstituted orsubstituted by one to five substituents selected from the groupconsisting of alkyl of l to 4 carbon atoms, the same or differenthalogen, the same or different haloalkyl of l or 2 carbon atoms and 2 toS halogen atoms, alkoxy of l or 2 carbon atoms, the same or differenthaloalkoxy of l or 2 carbon atoms and 2 to 5 halogen atoms nitro andamino or aryl substituted by phenyl and halophenyl; and

Y is CO, O-NOH or C(OH),,

According to another embodiment of the present invention X and X areeach hydrogen;

R is phenyl unsubstituted or substituted by l to 5 halogeno moieties, byone to three members selected from the group consisting of alkyl of l to4 carbon atoms, fluorine, chlorine, bromine, iodine, trifluoromethyl,alltoxy of l or 2 carbon atoms and nitro, or by amino, phenyl,chlorophenyl or bromophenyl.

R is hydrogen or phenyl;

R is alkyl of l to 4 carbon atoms..Phenyl or chlorophenyl; and Y is asabove defined.

According to another embodiment of the present invention,

X and X are each hydrogen;

R is phenyl unsubstituted or substituted by l to 3 fluorine, chlorine,bromine, methyl, t-butyl, and trifluoromethyl moieties or by nitro orphenyl;

R is hydrogen or phenyl;

R is methyl, t-butyl, phenyl or chlorophenyl; and

Y is as above defined.

According to another embodiment of the present invention,

X and X are each hydrogen;

R is phenyl, chlorophenyl, dichlorophenyl, trichloroph'e'n yl,tetrachlorophenyl, pentachlorophenyl,

- fluorophenyl, bromophenyl, chloromethylphenyl,

chlorodimethylphenyl, dic'hlorotrifluoromethylphenyl, chlorobromophenyl,chloronitrophenyl,

trifluoromethylphenyl," 'dichlorotrifluoromethylphenyl, tolyl,dimethylphenyl,t-butyl, phenyl, me-

' thylnitrophenyl,methoxyphenyl, aminophenyl, di-

phenylor phenylbromophenyl;

' R is hydrogen or'phenyl; I

R is methyl, t-bu tylphenyl or chlorophenyl;- and Y-isas above defined.

A ccordingto a particularly preferred embodiment of e present invention,

v Xand X are each hydrogen;

R is phenyl, "unsubstituted or substituted by one to five and preferablyone to three substituents selected from the group consisting offluorine, chlorine, bromine, methyl, t-butyl, trifluoromethyl, nitro andphenyl;

R is hydrogen or phenyl;

R is methyl, t-butyl, phenyl or chlorophenyl; and

5 Y is a keto group a keto-hydrate group C(OH),),

or a keto-oxime group C=NOH), and hydrochloride salts thereof.

The pharmaceutically acceptable non-toxic salts of S andl,5-naphthalenedisulphonic acid. Thus the preterred salts according tothe present invention include the hydrochloride, the hydrobromide, thephosphate, the nitrate, monofunctional and bifunctional carboxylates,hydroxycarboxylates, for example, the acetate,

maleate, succinate, fumarate, tartrate, citrate, salicylate, sorbate andlactate and l,5-naphthalenedisulphonate. V

The following compounds are representative of those of the presentinvention:

The 1,2,4-triazoles of the present invention can be produced by a numberof'processes of whichfour'are illustrated below..These processesaredisignated (a),

(b), (c) and (d) for con v erii entieii-l Hal] wherein R, R, R and,Y-are as above defined and wherein X andx' are as above defined, inequimolz 6 wherein X and X are as above defined, accordin to techniquesper se known generally in molar amounts either in the presence or in theabsence of an acid binding' agent such as, for example, triethylamine oran excess of tria'aole and in the presence of a polar solvent forexample, aoetonitrile at a temperature of from about 20C to about l'C,preferably at about C to about C. The product is isolated by evaporatingthe reaction mixture in vacuo and picking up the resi- 10 due in anorganic solvent, for example, methylenechloride. The resulting solutionis extracted by shaking witr water to remove the trlazole halide formedand the organlc phase is again distilled in vacuo. The oil which remainsafter the solvent has passed over is purified either according totechniques per se known via the sal or by recrystallization, forexample, from ether.

According to process (b), a compound of the for mula:

I R10-C-Y-R3 wherein R, R, R, and Y are as above defined, is re actedwith a l,2',4-triazole of formula lll above in 1 manner per se known,generally in molar amounts ei ther in the presence or in the absence ofa dehydratin agent, for example, calcium oxide and either in th presenceor in the absence of a high boiling solven such as chlorobenzene, butpreferably in the absence 0 such a solvent, especially in the melt, at atemperatur of from about 100C to about 230C, preferably be tween about Cand about 200C. The resultin products are isolated and purified asdescribed abov under process (a).

According to process (c), a compound of the formul IV is reacted with athionylbistriazole of the formula proportions either-in the presence orin the absence r a solvent, for example, acetonitrile or benzene at aten peratureof from about 20C to about 100C. The prot uct is isolatedand'purified according to procedures p4 se known and which have beendescribed above und process (a);

According to process (d), a compound of the to Halis halogen, especiallybromine or chlorine is remum acted with a l,2,4-triazole of the formula:60

(ills l (In) tt o-c-v-n (v N J,oyu,444

wherein R, R, R and Y are as above defined, is reacted with thehydrochloride of a l,2,4-triazole of the formula lll, generally inapproximately molar amounts,

' either in the presence or in the absence of a diluent such as dioxaneor dibutyl ether and in the presence of an acid catalyst, for example,p-toluenesulphonic acid, but preferably in the melt, at a temperature offrom about 80C to about 250C, preferably between about 120C and 200C.The reaction product is isolated and All starting compounds used for theproduction of IS the l,2,4-triazoles of the present invention are eitherknown or obtainable according to known methods.

For example, compounds of formula II can be obtained by reacting analcohol of the formula:

I) wherein R is as above defined, or the sodium alcoholate of thealcohol with, for example, an approximately molar amount of a compoundof the formula:

wherein R, R and Hal are as above defined in a manner per se known, forexample, in ethyl acetate at the boil. The active hydrogen atomwhichstill remains can subsequently be replaced by halogen according totechniques per se known, for example, by heating with elementary bromineto about 140C. The keto group can if desired be converted into afunctional derivative and the desired product is purified and isolatedaccording to the procedures described above or those which are known.

Compounds of the formula N which are used as starting materials can beobtained according to procedures per se known from a halogen derivativeof the formula ll. They can also be produced by procedures per se known,for example, by reacting a,B-diketones or a-ketoaidehydes with alcoholsacc rding to the following reaction mechanism:

(vnr) wherein R, R and R are as above defined.

if desired, the keto groupis converted into a functional derivativeaccording to techniques per se known.

The thionyl-bis-l ,2,4-triazoles of the formula V which can be used asstarting compounds can be produced according to known processes (compareAngew. Chem. 68, page 754 (i956), for example from the appropriatetriazole and thionyl chloride in tetrahydrofuran at room temperature.

The compounds of the formula V] which can be used methods (compare, forexample, 1. Chem. Soc. (London) (1970), 3, pages 462 to 464 and LiebigsAnn. Chem. 735 (i970), pages 149, I55, I56, Krbhnke, Journal f.praktische Chemie Bd. II (1960), 249-255 The triazoles of the formulaiii are either known or obtainable according to procedures per se known.

The l,2,,4-triazoles of the present invention exhibit a broadantimycotic spectrum of activity against annualpathogenic fungi,especially against dermatophytes and blastomycetes as well as againstbiphase fungi, for example, against species of Candida such as Candidaalbicans, species of Epidermophyton such as Epidermophyton floeeosum,species of Aspergillus such as Arpergillus niger, species ofTrichophyton such as Trichophyron mentagrophytes, species of Microsporonsuch as Mlerosporon felineum and species of Peniclliium such asPeniclliium commune.

The l,2,4-triazoles of the present invention are useful for thetreatment of derrnatomycoses and systemic mycoses in humans and animalscaused by Trichophyton menragrophyres and other species of Trichophyton,species of Microsporon, Epidermophyton floccosum, blastomycetes andbiphase fungi as well as moulds.

The pharmaceutical compositions of the present invention contain a majoror minor amount e.g. 99.5% to 0.1%, preferably 95% to 0.5% of at leastone l,2,4 triazole as above defined in combination with apharmaceutically acceptable non-toxic, inert diluent or carrier, thecarrier comprising one or more solid, semisolid or liquid diluent,filler and formulation adjuvant which is non-toxic, inert andpharrnaceutically acceptable. Such pharrnaceutical compositions arepreferably in dosage unit form; i.e., physically discrete unitscontaining a predetermined amount of the drug corresponding to afraction or multiple of the dose which is calculated to produce thedesired therapeutic response. The dosage units can contain one, two,three, four or more single doses or, alternatively, one half, third orfourth of a single dose. A single dose preferably contains an amountsufficient to produce the desired therapeutic effect upon administrationat one application of one or more dosage units according to apredetermined dosage regimen, usually a whole, half, third or quarter ofthe daily dosage'adm'inistered once, twice, three or 7 four times aday.Other therapeutic agents can also be present.

Although the dosage, and dosage regimen must in each case be carefullyadjusted, utilizing sound professional judgment and considering the age,weight and condition of the recipient,- the route of administration andthe nature and gravityof the illness, generally the dosage will be from30 to 250, and preferably 50 to 200, mg/kg of body weight per day. insome instances a sufficient therapeutic effect can be obtained at alower dose while in others, a larger dose will be required.'

Oral administration can be effected utilizing solid and liquid dosageunit forms such as powders, tablets, dragees, capsules, granulates,suspensions, solutions and the like.

Powders are prepared by comminuting the compound to a suitable fine sizeand mixing with a similarly comminuted pharmaceutical carrier such as anedible carbohydrate as for example starch, lactose, sucrose, glucose ormannitol. sweetening, flavoring, preservaas starting compounds can beproduced by customary tive, dispersing and coloring agents can also bepresent.

Capsules are made by preparing a powder mixture as described above andfilling formed gelatin sheaths. Glidams and lubricants such as colloidalsilica, talc, magnesium stearate, calcium stearate or solid polyethyleneglycol can be added to the powder mixture before the filling operation.A disintegrating or solubilizing'agent such as agar-agar, calciumcarbonate or sodium carbonate can also be added to improve theavailability of the medicament when the capsule is ingested.

Tablets are formulated for example by preparing a powder mixture.granulating or slugging, adding a lubricant and disintegrant andpressing into tablets. A powder mixture is prepared by mixing thecompound, suitably comminuted, with a diluent or base as describedabove, and optionally with a binder such as carboxymethyl, cellulose, analginate, gelatin, or polyvinyl pyrrolidone, a solution retardant suchas paraffin, a resorption accelerator such as a quaternary salt and/oran absorption agent such as bentonite, kaolin or dicalcium phosphate.The powder mixture can be granulated by wetting with a binder such assyrup, starch paste, acacia mucilage or solutions of cellulosic orpolymeric materials and forcing through a screen.'As an alternative togranulating, the powder mixture can be run through the tablet machineand the resulting imperfectly formed slugs broken into granules. Thegranules can be lubricated to prevent sticking to the tablet formingdies by means of the addition of stearic acid, a stearate salt, talc ormineral oil. The lubricated mixture is then compressed into tablets. Themedicaments can also be combined with free flowing inert carriers andcompressed into tablets directly without going through the granulatingor slugging steps. A clear or opaque protective coating consisting of asealing coatof shellac, a coating of sugar or polymeric material and apolish coating of wax can be provided. Dyestuffs can be added to thesecoatings to distinguish different unit dosages.

Oralfluids such as solutions, syrups and elixirs can be prepared indosage unit form so that a given quantity contains a predeterminedamount of the compound.

Syrups can be prepared by dissolving the'compound in a suitably flavoredaqueous sucrose solution while elixirs are preparedthrough the use'of anon-toxic alcoholic vehicle. Suspensions can be formulated by dispersingthe compound in'a non-toxic vehicle. Solubilizers and emulsifiers suchas ethoxylated isostearyl alcohols and polyoxyethylene sorbitol esters,preservatives, flavor additives such as'peppermint oil orsaccharin, andthe likecanalso be added.

Where appropriate, dosage unit formulations for oral administration canbe 'microencapsulated. The formulation can also be prepared'to prolongor sustain the release as for example bycoating or embedding particulatematerial in polymers,wax or the like.

Parenteral administration can be effected utilizing liquid dosageunit'forms such assterile solutions and suspensions intended forsubcutaneous. intramuscular or intravenous injection. These are preparedby suspending or dissolving a measured amount of the compound in anon-toxic liquid vehicle suitable for injection such as an aqueous oroleaginous medium and sterilizing the suspension or solution.Alternatively, a measured amount of the compound is placed in a vial andthe vial and its contents are sterilized and sealed. An accompanyingvial or vehicle can be provided for mixing prior to administration.Non-toxic salts and salt solutions can be added to render the injectionisotonic. Stabilizers, preservatives and emulsifiers can also bf added.

Rectal administration can be effected utilizing sup positorles in whichthe compound is admixed with lov melting water soluble or insolublesolids such as poly ethylene glycol, cocoa butter, higher esters as forex ample myristyl palmitate, or mixtures thereof.

Topical administration can be effected utilizing solit dosage unit formssuch as powders or liquid or semiliq uid dosage unit forms such assolutions, suspensions ointments. pastes, creams and gels. The powdersart formulated utilizing such carriers as talc, bentonite, si licicacid, polyamide powder and the like. Liquid ant semiliquid formulationscan utilize such carriers, in ad dition to those described above, aspolyethylene glycol vegetable and mineral oils, alcohols such asisopropa nol and the like. Other excipients such as emulsifierspreservatives, colorants, perfumes and the like can aiS( be present.Formulations can also be administered a. an aerosol, utilizing the usualpropellants such as ihl chlorotluorohydrocarbons.

The preferred daily dose is 1.5 to 22.5 g., prefcrabl 2.5 to 18.0 g. ofactive agent.

While the routes of administration include oral, pa renteral (i.e.,intramuscular, intraperitoneal, and intra venous), rectal, and topical,oral administration am topical application are particularly preferred.

The preferred pharmaceutical compositions ar therefore those in a formsuitable for oral administra tion such as tablets and suspensions andthose suitabl fortopical application such as ointments.

The antimycotic activity of representative corr p'ounds'according to thepresent invention is demor strated from the followinginvitro and in vivoexper mental data:

1. Determination of the anti-mycotic action spectrui in vitro by theseries dilution test.

Description of the experiment:

The nutrient substrates used were Sabourauds milie d'e'preuve forderrnatophytes and mould fungi an meat brothglucose bouillon forblastomyces and b phase fungi. The incubation temperature was 28C ar theincubation time was 24 to 96 hours.

The results of the experiments are summarized Table A.

Table A Minimum inhibitory concentration in 'ylml'of nutrient medium(MlC) Table A-Continued Minimum inhibitory concentration in 71ml ofnutrient medium (MIC) Compound from Trichuplrylmr Candida PrmilliumArprrgillus Mirmspumn Example No.: menlugropllyles alhirum mnmmnr nigrrHinrlml n.s. w.s. n s. w.s. n s Wat.

9 8 32 I 64 64 I2 (I l I00 W0 W0 40 ll!) 40 I5 32 32 64 64 I I7 32 64 6464 64 2i 8 64 64 64 64 27 4 4 40 I00 l00 IN I) 32 64 64 64 Legend: w.s.with 30' serum added mt. I no serum udded 90] inhibition of growth.

2. Antimyconc action of the compounds of the inven- The experimentalresults are summarized in Table D:

tion. in animal experiments.

a. Topical application in experimental trichophytosis of guinea pigs(pathogen: Trichophyron metagrophytes) 2o Table D Description of theexperiment:

A 1% strength solution of the active compounds in a guimtcnndidoslsomice f dimethylsulphoxide/glycerine/water mixture (1:3:6) or Compound fmMM 3" in polyethylene glycol 400 was applied locally for l l to mm l4days after the trichophytosis had been produced exr I2 perimentally. w

The experimental results are shown in Table B. 6

Table B 9 H Legend Action of the compounds in which can used accordingto the m .nmm invention. in trichophytoals of guinea pigs m "M on "a wby Mm Compound form Action against Trichophyton Example No. mentagmphymThe following are examples of pharmaceutical com- 5% *II" positionsaccording to the invention:

a. 1% strength solution for topical treatment w Sufficient polyethyleneglycol 400 is added to l g of IL. 111T:LZ2,Y:.'{,T{T;,.{: the compoundproduced in Example 27. while stirring -H++ I complete suppression ofsymptoms ofthe infection and warming slightly, O NO I total Of 100 ml OfSOlU- a 40 tion.

b. Action. on oral administration. on Quinckeanum b. 1% strengthointment for topical treatment trichophytosis of white mice. 1 g of thecompound produced in Example 27 is grolt was possible to suppress thedevelopment of the und .with 5g of viscous paraffin oil. Thereaftersuffi- Quinckeanum infection in mice [with doses of 100 'cient ointmentbase of paraffin oil and polyethylene mg/kg of body weight given orallytwice daily up to the glyeolis added to give a total of 100 g'ofointment.

eighth day of the infection. c; 10% strength suspension syrup for oraladministra- The result can be seen from Table C. p v tion 7 i 7 Table cI I .jSufficient plant oil isadded to a mixture of 10 g of the activecompound producedin Example 12 and 0.05 g

Action of the compounds of the invention in butnckeanum so umaccharinand a of colloidal silica and mmop'hymk r w t i g of peppermintoil, to give a total of 100 ml of suspen- Com ound from Oral actionagainst Trisionsyrup. 6 i

Exa mple No. chophylon mentagmphyles I an'cxample mgfhcamcm m age unitform according to the invention: 12 d. Tabletcon'taining 200 mg ofactive compound, for 27 oral administration '2 g of the compoundproduced in Example 12, l g of For explanation of symbols. see Table Blactose and 0.3 g of corn starch are granulated with 0.1 c. Candidosisof mice. g of corn starch gluten. The mixture is forced throughDescription of the experiment: a sieve of about 4 to-6 mm mesh width andis dried.

Mice of Type SPF-CF. were intravenously infected This dried mixture ishomogenized through a sieve of with 1-2 X 10' logarithmically growingCandida cells 0.8 to 1 mm mesh width and is then mixed with 0.15 gsuspended in physiological sodium chloride solution. of starch and 0.02g of magnesium stearate. The mix- One hour before and 7 hoursaft'erinfection the aniture thus obtained is pressed-to give 10 tablets. malswere treated orally with 2 X mg of the prepa- The remaining1,2.4-triazoles according to the presrations/kg of body weight. I entinvention may be formed into pharmaceutical com- Untreated animals 'diedof the infection 3 to 6 days positions and into compositions inunitdosage form in after infection. The survival rate on the 6th day afterina similar manner. fection was about 5% in the case of untreatedcontrol The following non-limitative examples more particuanimals. larlypoint out and illustrate the present invention:

13 EXAMPLE 1 l c1- Q-o-cn-co-c(cu 11.2 g (0.033 mol) ofl-bromo-l-(2',4'- dichlorophenoxy)-3,3-dimethyl-butan-2-one and 9.9 g(0.15 mol) of 1,2,4-triazole are dissolved in 80 ml of acetonitrile andthe solution is heated under refiux for 48 hours. Thereafter the solventis distilled off in vacuo, the residue is taken up in 150 ml of waterand the aqueous solutionis extracted by shaking three times with 40 mlof methylene chloride at a time. The organic phase is thereafter twicewashed with 150 ml oflwgter at a time, dried over sodium sulphate anddistil e The oil obtained as a residue is fractionally recrystallisedfrom a little ether, whereby first l g of a product of melting point145C, which, being a by-product was not identified, is obtained,followed by 7.6 (70% of theory) ofl-[(2',4'-dichloro)-phenoxy]-l-[l',2',4'-triazolyl-(l')]-3,3-dimethyl-butan-2-one of melting point 65C.

The starting compound of the formula 01- Q-o-cn-co-c ca;

(0.2 mol) of 2,4-dichlorophenol and 4.6 g (0.2 mol) of sodium in 130 mlof absolute alcohol, and the mixture is heated to the boil overnight.Thereafter, the sodium bromide produced is filtered off hot, thefiltrate is distilled in vacuo and the solid residue is recrystallisedfrom a little ligroin.

- 38 g (73% of theory) of .l-(2',4'-dic hlorophenoxy)-3,3-dimethyl-butan-2-one of melting point65C are obtained. 6 ml (0.1 1mol) of bromine areadded to 26.1 g (0.1 mol) ofl-(2',4'-dichlorophenoxy)-3',3-dimethylbutan-Z-one and the mixtureisheatedforl hour to 140C under reflux. The resulting oily residueis-talten up in petroleum ether, whereupon it c rystallises;.the solidresidue is filtered off and well rinsed. 1

30 g (89% of theory) of l-bromo-l -(2',4 dichlorophenoxy)3-dimethyl-butan-2-one of melting point 70C are thus obtained.

The remaining starting compounds of this type are obtainable in the samemanner.

Production of the hydrochloride of the compound from Example 1:

C l a l-[ 2 ',4'-Dichloro)-phenoxy]- l l ',2',4'-triazolyl-(l)l-3.3-dimethyl-butan-2-one is suspended in anhydrous ether andhydrochloric acid in ether is adder Hereupon, solution gradually occurs.The solvent is dis tilled ch in vacuo. The residue left is recrystallisefrom iso-propanol.

The [i-[(2',4'-dichloro)-phenoxy]- l 1,2',4 triazolyl-( l')]-3,3-dimethyl-butan-2-one] hydfOChk ride thus obtained has a meltingpoint of 125 to 127( EXAMPLE 2 rm f) Ol-Q-O-OH-OO-MQHQ,

l7.7 g (0.05 mol) of l,l-bis-(4'-chlorophenoxy)-3,1 dimethyl-butan-Z-oneare intimately mixed with 5.9 (0.055 mol) of 1,2,4-triazolehydrochloride and th mixture is heated to 220C over the course of 1 hotand left at this temperature for 30 minutes; in tl course thereof, the4-chlorophenol eliminated boils.

After cooling, 100 ml of 10% strength sodium h; droxide solution areadded and this is covered with 2C ml of ether. The ether phase isseparated off ar washed with three 30 ml portions of 5% strength s diumhydroxide solution and two 50 ml portions of w ter. After drying oversodium sulphate, the solvent distilled off in vacuo. The oily residue istaken up lOO ml of anhydrous ether and 0.055 mol of hydrogt chloride ispassed into this solution. This gives a preci itate which afterstandingovemight is filtered off at rinsed with ether.

7.3 g (46% of theory) of [l-[4'-chlorophenoxy]- [l',2',4'-triazolyl-( l)]3,3-dimethyl-butan-2-one1 h drochloride of melting point 103 to 105Care 0 tained.

The starting compound of the formula:

H-CO-C CH is produced as-follows:

6.5 g (0.2 mol) of strength sodium hydride suspended in ml of anhydrousacetonitrile and g'(0.21 mol) of 4-chlorophenol in 50 ml of acetonitiare added dropwise-at room temperature whilst stirr and cooling.

After completion of the evolution of hydrogen, a f

'ther 27 g (0.105mol) of l,l-dibromo-3,3-dimetl butan-Z-one (produced ina known manner, for exa ple according to Organic Synthesis, 10, page12). added whilst'stirring and cooling. Thereafter the n ture is slowlyheated to the boil and is boiled for hours under reflux.

After cooling, the solvent is distilled off in vacuo, residue is boiledup with'hot ethyl acetate, active cl coal is added, the mixture isfiltered and is again b0 up briefly and the solution is distilled firstin vacuo a aher the solvent has passed over, in a high vacuun 54 g(76.5% of theory) of l,l-bis-(4'-chlorophenoxy)-3,3-dimethyl-butan-2-one of boiling point 150C (0.1 mmHg) are obtained. The viscous oil solidifies after some time.

The remaining starting compounds of this type can be obtained in thesame manner.

EXAMPLE 3 18.0 g (0.05 moi) ofw-bromo-u-(2',6'-dichlorophenoxy)-acetophenone and 15 g (0.22 mol) of1,2,4- triazole are dissolved in 120 ml of acetonitrile and heated underreflux for 48 hours. After distilling off the solvent in vacuo. theresidue is taken up in 400 ml of water. This aqueous solution isextracted with methylene chloride as described, the organic phase iswashed with two 100 ml portions of water and then dried over sodiumsulphate, and the solvent is distilled off in vacuo. The resulting oilyresidue crystallises on heating with ether.

After recrystallisation from ethylene chloride, 7 g of theory) of m-[(2',6'-dichlorophenoxy)l-m- [1',2',4-triazoly1-( l ')]-acetophenone ofmelting point 130C are obtained.

The w-Brorno-w-(2',6'-dichlorophenoxy)- acetophenone used as thestarting material is produced by condensation of 2,6-dichlorophenol withw-chloroacetophenone and bromination of the resulting (0)(2',6'-dichlorophenoxy)-acetophenone in a customary and known manner, andhas a melting point of 58C.

The remaining starting compounds of this type are obtainable in the samemanner.

EXAMPLE 4 39 g (0.12 mol) of l-bromo-l-(4'-tert.-butylphenoxy)-3,3-dimethyl-butan-2-one and 24 g (0.35 mol) of1,2,4-triazole are dissolved in 240 ml of acetonitrile and the solutionis heated to the boil under reflux for 24 hours. Thereafter the solventis distilled in vacuo, ice water is added to the residue and the mixtureis extracted with three 40 ml portions of methylene chloride. Theorganic phase is separated off and washed with two 200 ml portions ofwater and dried over sodium sulphate, and the solvent is distilled offin vacuo.

The residue is recrystallised from ligroin. 26 g (69% of theory) ofl-[(4'-tert.-butylphenoxy)]-1-[l',2',4'- triazolyl(l)]-3.3-dimethyl-butan-Z-one of melting point 115C are obtained.

l-Bromol -[4' -tert.-butylphenoxy)]-3,3-dimethylbutan-2-one (meltingpoint C), used as the starting material. is obtained by condensation ofp-tbutylphenol with -bromopinaco1one-(2) and subsequent brominstion.

The remaining starting compounds of this type are obtainable in the samemanner.

EXAMPLE 5 I (ll-Q-O- llama 19.0 g (0.05 mol) ofl-bromo-l-(4'-chlorophenoxy)- 1-phenyl-3,3-dlmethyl-butan-2-one aredissolved in ml of acetonitrile. 12 g (0.175 mol) of 1,2,4- triazole arethen added and the solution is heated under reflux for 12 hours. Afterdistilling off the solvent in vacuo, 200 ml of ice water are added.Thereafter the mixture is extracted with four 50 ml portions ofmethylene chloride and the organic phase is separated off and washedwith-three 50 ml portions of water. It is dried and the solvent isdistilled off in vacuo. The oily residue is recrystallised from ligroin.

5.3 g (29% of theory)- of 1-[4'-chlorophenoxy)]-l- [phenyll-l-ll',2,4-triazolyl(1')]-3,3-dimethylbutan-2-one of melting point C areobtained.

The starting material of the formula CI-Q-O- til-cum is produced asfollows:

The Grignard compound is produced from 38 g (0.3 mo1)of benzyl chlorideand 7.3 g (0.3 mol) of magnesium in 300 ml of anhydrous ether. 21 g(0.25 mol) of .pivalonitrilein 100 ml of anhydrous ether are addeddropwise thereto at theboil and the mixture is kept boiling under refluxfor 3 hours.

After cooling, the reaction mixture is introduced into 1.5 litres of icewater, the ether phases is separated off and discarded and the aqueousphase is stirred for 2 hours 'on a water bath. in the course thereof,the mixture gradually assumes an oily consistency. The oil is repeatedlyextractedwith 250 ml of methylene chloride and the organic phase iswashed with water, dried and subjected to vacuum distillation.

40.5 g (92% of, theory) of 'l-phenyl-3,3-dimethylbutan-2-one of boilingpoint (18 mm Hg) 86 to 88C are obtained.

17.6 g (0.1 mol) of l-phenyl-3,3-dimethyl butan- 2-one are dissolved in100 m1 of carbon tetrachloride, 5 ml (0.1 mol) of bromine are addeddropwise thereto whilst stirring and under reflux, and the mixture isheated to the boil for one hour. After cooling, and distilling off thesolvent, 25.4 g of 1-bromo-1-phenyl-3,3- dimethyl-butan-Z-one of meltingpoint 38 to 42C are obtained in quantitative yield.

A solution of 25.4 g 0.1 mol) of l -bromo-I phe nyI from ligroin. 20.2 g(67% of theory) of 1- 3,3-dimethyl-butan-2one in 50 ml of ethyl acetateis chlorophenoxy)]-l-lphenyl1-3.3-dimethyl-butanadded dropwise, at theboil, to a solutionof 12.85 g Z-one of melting point l03'C are obtained.(0. 1 mol) of 4-chlorophenol and 2.3 g (0.1 mol) of so- Other startingmaterials of this type are obtainable dium in 100 ml of ethanol. Afterboiling for 12 hours 5 an analogous manner. under reflux. the sodiumbromide which has separated The compounds'aet forth in Table l areproduced a out is filtered off hot. The filtrate is distilled in vacuocording to an analogous procedure from that describ and the solidresidue which remains is recrystallised in Examples 1 to 5.

Table 1: x2

l 1 x l R1-0-C-Y-R3 L2 Elzqmmple a n a r v x, Melting Point c O- I I 6c1 Q a e10 co ii a 101 104 c1 1 7 u' cum co a u 136 8 Br H c (cn )3 co u11 a9 92 t I a t 9 H m h H 11 12123 1 CH3 1 I 10 010 H t;(cn co u .11 9496 11 0 1/ 9mg), I co u u 145 12 I g (x011 co n; a 105 106 0 x l I H 7073 14 1 C1 ll l CO H: ii liytiiggchlofide 15 3 v (X083): 00 H ii 62 t Ia 11 1 t 16 a c(ca I. co u u o in combination .with apharmaceutically-acceptable,

23 24 was Example No. a a R r x x halting Point c 49 N H (K011 CO H h'filtrate 140-141, decomposition 50 0 li H C(UH 00 H H LS-Mphthalenedisulhonate 255, ecompoaition 51 01 ii C(UlL 3 00 H H sulphate 52 c1 11 cum00 a H nitrate 133, decomposition Cl 53 01 a ctcii so a a1,5-Naphthalenediaulphonate Y C]. 250, decomposition What is claimed is:

1. An antimycotic composition which comprises an antimycotlcallyeffective amount of a l,2,4-triazole of the formula:

l k i 1 I X l R O-liI-Y-R or a pharmaceutically-acceptable, nontoxicsaltthereof, wherein X is hydrogen or alkyl of l to 3 carbon atoms;

X, is hydrogen or alkyl of l to Scarbon atoms;

R is phenyl or phenyl'substituted by one to five substituents selectedfrom the group consistingof alkyl of l to 4 carbon atoms, the sameordifi'erent halo- '50 gen, the same or different haloalltyl of l .or 2carbon atoms and 2 to 5 halogen atoms, alltoxy of l or 2 carbon atoms,the same or different haloalkoxy of l or 2 carbon atoms and 2 'to 5halogen atoms, and nitro, orv by one substituent'selected from the groupconsisting of phenyl, halophenyl and amino; 2 is hydrogen or alkyl of lto 6 carbon atoms;

R is alkyl of l to 6 carbon atoms; and

Y is CO;

nontoxic, inert diluent or carrier.

2. A composition according to claim 1 wherein X and X are each hydrogen;R is phenyl or phenyl substituted by l to 5 halogeno moieties, by one tothree substituents selected from the group consisting of alltyl of l to4 carbon atoms, fluorine, chlorine, bromine, iodine, trifluoromethyl,alltoxy of l or 2 carbon atoms, and nitro, or by amino phenyl,chlorophenyl or bromophenyl; R is hydrogen; and R is alkyl of l to 4carbon atoms. 3. A composition according to claim 1 wherein R is phenylor phenyl substituted by one to three substituents selected from thegroup consisting of fluorine, chlorine, bromine, methyl, t-butyl andtrifluoromethyl, or by nitro or phenyl; and R is methyl or. t-butyl. 4.A'composition according to claim 1 wherein R is phenyl, chlorophenyl,dichlorophenyl, trichlorophenyl, tetrachlorophenyl, pentachlorophenyl,

'fluorophenyl, bromophenyl, chloromethylphenyl, chlorodimethylphenyl,dichlorotrifluoromethylphenyl, chlorobromophenyl, chloronitrophenyl,trifluoromethylphenyl, dichlorotrifluoromethylphenyl, tolyl,dimethylphenyl, t-butylphenyl, me-

thylnitrophenyl, methoxyphenyl, aminophenyl, diphenyl orphenylbromophenyl; and

R methyl or t-butyl.

5. A composition according to claim 1 wherein the l,2,4-triazole is'inthe form of a salt and said salt is selected from the group consistingof the hydrohalides, the phosphates, nitrates, monofunctional anddifunctional carboxylates, hydroxycarboxylates and l,5-naphthalenedisulphonate.

6. A composition according to claim 5 wherein the salt is selected fromthe group consisting of the hydrochloride, thehydrobromide, thephosphate, nitrate, acetate, maleate, succinate...fumarate, tartrate,citrate, salicylatefsorbate, lactate and 1,5-naphthalenedisulphonate,. Y

7.". A composition according to claim 1 wherein the l,2',4 triazole. isin the form of the hydrochloride salt.

8. 'l'he'composition according to claim 1 wherein the 1,2,4-triazole isl-[(2',4'-dichloro)-phenoxy1-1- l ',2',4'-triazolyl-( l')1-3,3-dimethyl-butan-2-one or the hydrochloride salt thereof.

9. A composition according to claim 1 wherein the 1,2,4-triazole is ofthe formula:

wherein X is hydrogen; X is hydrogen;

Ris

o- R is hydrogen; I

R is C(CHQ and Y is CO. i

10. A composition according to claim lwhcrei'n the 1,2,4-triazole is ofthe formula:'

wherein X is'hydrogen; X is hydrogen; R is R is hydrogen;

R is C(CH and n Y is CO, i 11. A composi 1,2,4-triazoie is'ofIthe'1formule:

wherein V X is hydrogen; X is hydrogcm R is R is hydrogen; 7 R isC(CH,),; and Y to CO.

tion" sccording j the I is 12. A composition according to claim 1wherein the 1,2.4-triuolc is of the formula:

L i I I i w R O -C-Y-R 2' I. 2 wherein X is hydrogen; X is hydrogen; ii.is

tociaim' 1 wherein th rmula.

whereinq T I X is hydrogen;

A composition according to claim I in oral ad phenyl, tolyl,dimethylphenyl, t-butylphenyl, memimstration form. thylnitrophenyl,methosyphenyl, aminophenyl, di-

16. A composition according to claim 1 in topical apphenyl orphenylbromophenyl; and plication form. R methyl or t-butyl.

17. A composition according to claim 1 in the form 5 23. A methodaccording to claim 19 wherein the of a tablet. l,2,4-triazole is in theform of salt and said salt is se- 18. A composition according to claim17 wherein lected from the group consisting of the hydrohalides, eachtablet contains 200 ml of active agents. the phosphates, nitrates,monofunctional and difunc- 19. A method of treating mycoses in humansand anitional carboxylates, hydroxycarboxylates and mals which comprisesadministering to said human or l,5-naphthalenedisulphonate.

animal an antimycotically effective amount of 1,2,4- 24. A methodaccording to claim 23 wherein the salt tnazole of the formula: isselected from the group consistingof the hydrochloride, thehydrobromide, the phosphate, nitrate, acetate.

- 2 maleate succinate, fumarate, tartrate, citrate, salicyl5 late,sorbate, lactate and l,S-naphthalenedisulphonate,

I 25. A method according to claim 19 wherein the IL 1,2,4 -triazole isin the form of the hydrochloride salt.

26. The method according to claim 19 wherein the l I X T l,2,4-triazoleis i-[(2',4'-dichloro)-phenoxyl-l- 3[l',2',4'-trizolyl(l')]-3,3-dimethyl-butan-2-one or the R O-C-Y-R or thehydrochloridesalt thereof.

2 27. The method according to claim 19 wherein the R l,2,4-triazole isof the formula:

or a pharmaceutically-acceptable, nontoxic salt 25 thereof, wherein X ishydrogen or alkyl of l to 3 carbon atoms; I l X is hydrogen or alkyl ofl to 3 carbon atoms; R is phenyl or phenyl substituted by one to fivesub- 1 T stitutents selected from the group vconsisting of 1 3 alkyl ofl to 4 carbon atoms, the same or different halogen, the same ordifferent haloalltyl of l or 2 2 carbon atoms and 2 to 5 halogen atoms,alkoxy of D l or 2 carbon atoms, the same or different haloalkoxy of lor 2 carbon atoms and 2 to 5 halogen y g atoms, and nitro, or by onesubstituent selected is hydrogen: from the group consistng of phenyl,halophenyl and R is amino; R is hydrogen or alkyl of l to 6 carbonatoms; p R is alkyl of l to 6 carbon atoms; and 40 Y is CO; incombination with a .pharmaceutically-acceptable, i nontoxic, inertdiluent or carrier. s)ai and 20. A method according to claim 19 whereinI y i and 2 are each hydrogen; a 28. The method according to claim 19wherein the R is phenyl or phenylsubstituted by Ito 5 halogeno of theformula:

moieties, by one to threesubstituent s selected from the groupconsisting of alkyl of l to. 4 carbon atoms, fluorine, chlorine,bromine, iodine, trifluoromethyl, alkoxy of l or 2 carbon ator'ns'Qandnitro,- or .by amino, phenyl, chlorophenyl I orv bromo- I phenyl; I

2 is hydrogen; and a R is alkyl of l to 4 carbon atoms, 21. A methodaccording to claim 19 wherein R is phenyl or phenyl substituted by oneto three substituents selected fromthe group consisting of wh reinfluorine, chlorine, bromine, methyl, t-butyl and tri- X is hydrogen;fluoromethyl, or by nitro or phenyl; and X i hydrog n: R 'is methyl ort-butyl. R l 22. A method according to claim 19 wherein R is phenyl,chlorophenyl, dichlorophenyl, trichlorophenyl, 'tetrachlorophenyl,pentachlorophenyl,

' fluorophenyl, bromophenyl, chloromethylphenyl,

chlorodimethylphenyl, dichlorotrifluoromethyl- R is hydrogen; phenyl,chlorobromophenyl, chlor'onitroph'enyl, R is C(CH;),; and

trifluoromcthylphenyl, dichlorotrifluoromethyls, Y is CO.

29 I 30 29. The method according to claim 19 wherein the wherein1.2,4-triazole is of the fonnulaz X is hydrogen; X is hydrogen;

R is a R o- =-Y-.-R C

R R is hydrogen; wherein R is ind X is hydrogen; Y is CO. I I ishydrogcn; 32. The method according to claim 19 WhClCln th 1 is 31,2,4-trlazolels of the formula:

R is hydrogen; I l R is C(CHah; and Y Y is co. 30.-The method accordingto claim 19 wherein the !,2,4-triazole is of the formula: v i i 2 I R uL wherein N X is hydrogen; x I X is hydrogen;

R O-C-Y-R R X is hydrogen;

2 1 X 18 hydrogen. R 15 I I s hydrogen H3C\ I R i C(CH); and

Y j I Y is CO. I I 8 00; I -40 33. Ajmethod according toclaim'l9 whereinthe a l v rninistration'is oral.

is hydrogen; I I Y method according to claim 19 wherein the a( R isC(CH3)3' and I I m nistration 1s by- -topical application. I Y is COI f35. Am ethod accordng to claim 19 wherein the a( v b tabIeL-L' 31. Th thd d to cl 19 whe e the m 'l' m Yr I l 2 i T: z 22,25 mm X m 36. Arnethod-accordingto claim 35 wherein eac tablet contains 200 ml of activeagent.

X I I J'ItArnethod according to claim 19 wherein the a: I I; I I 5 tirnycot ically effective amount is from 300 to 25 wa s-v fi r" x II v I338.14 method according to claim 37 wherein the a: R O -C-Y-R gtimycotically effectiveamountisfrom to 200 mg/k *2 .perday.-fl'fi J .e ee a i. I I I

1. An antimycotic composition which comprises an antimycoticallyeffective amount of a 1,2,4-triazole of the formula:
 2. A compositionaccording tO claim 1 wherein X1 and X2 are each hydrogen; R1 is phenylor phenyl substituted by 1 to 5 halogeno moieties, by one to threesubstituents selected from the group consisting of alkyl of 1 to 4carbon atoms, fluorine, chlorine, bromine, iodine, trifluoromethyl,alkoxy of 1 or 2 carbon atoms, and nitro, or by amino phenyl,chlorophenyl or bromophenyl; R2 is hydrogen; and R3 is alkyl of 1 to 4carbon atoms.
 3. A composition according to claim 1 wherein R1 is phenylor phenyl substituted by one to three substituents selected from thegroup consisting of fluorine, chlorine, bromine, methyl, t-butyl andtrifluoromethyl, or by nitro or phenyl; and R3 is methyl or t-butyl. 4.A composition according to claim 1 wherein R1 is phenyl, chlorophenyl,dichlorophenyl, trichlorophenyl, tetrachlorophenyl, pentachlorophenyl,fluorophenyl, bromophenyl, chloromethylphenyl, chlorodimethylphenyl,dichlorotrifluoromethylphenyl, chlorobromophenyl, chloronitrophenyl,trifluoromethylphenyl, dichlorotrifluoromethylphenyl, tolyl,dimethylphenyl, t-butylphenyl, methylnitrophenyl, methoxyphenyl,aminophenyl, diphenyl or phenylbromophenyl; and R3 methyl or t-butyl. 5.A composition according to claim 1 wherein the 1,2,4-triazole is in theform of a salt and said salt is selected from the group consisting ofthe hydrohalides, the phosphates, nitrates, monofunctional anddifunctional carboxylates, hydroxycarboxylates and1,5-naphthalenedisulphonate.
 6. A composition according to claim 5wherein the salt is selected from the group consisting of thehydrochloride, the hydrobromide, the phosphate, nitrate, acetate,maleate, succinate, fumarate, tartrate, citrate, salicylate, sorbate,lactate and 1,5-naphthalenedisulphonate.
 7. A composition according toclaim 1 wherein the 1,2,4-triazole is in the form of the hydrochloridesalt.
 8. The composition according to claim 1 wherein the 1,2,4-triazoleis1-((2'',4''-dichloro)-phenoxy)-1-(1'',2'',4''-triazolyl-(1''))-3,3-dimethyl-butan-2-one or the hydrochloride salt thereof.
 9. A composition according toclaim 1 wherein the 1,2,4-triazole is of the formula:
 10. A compositionaccording to claim 1 wherein the 1,2,4-triazole is of the formula:
 11. Acomposition according to claim 1 wherein the 1,2,4-triazole is of theformula:
 12. A composition according to claim 1 wherein the1,2,4-triazole is of the formula:
 13. A composition according to claim 1wherein the 1,2,4-triazole is of the formula:
 15. A compositionaccording to claim 1 in oral administration form.
 16. A compositionaccording to claim 1 in topical application form.
 17. A compositionaccording to claim 1 in the form of a tablet.
 18. A compositionaccording to claim 17 wherein each tablet contains 200 ml of activeagents.
 19. A METHOD OF TREATING MYCOSES IN HUMANS AND ANIMALS WHICHCOMPRISES ADMINISTERING TO SAID HUMAN OR ANMAL AN ANTIMYCOTICALLYEFFECTIVE AMOUNT OF 1,2,4-TRIAZOLE OF THE FORMULA:
 20. A methodaccording to claim 19 wherein X1 and X2 are each hydrogen; R1 is phenylor phenyl substituted by 1 to 5 halogeno moieties, by one to threesubstituents selected from the group consisting of alkyl of 1 to 4carbon atoms, fluorine, chlorine, bromine, iodine, trifluoromethyl,alkoxy of 1 or 2 carbon atoms, and nitro, or by amino, phenyl,chlorophenyl or bromophenyl; R2 is hydrogen; and R3 is alkyl of 1 to 4carbon atoms.
 21. A method according to claim 19 wherein R1 is phenyl orphenyl substituted by one to three substituents selected from the groupconsisting of fluorine, chlorine, bromine, methyl, t-butyl andtrifluoromethyl, or by nitro or phenyl; and R3 is methyl or t-butyl. 22.A method according to claim 19 wherein R1 is phenyl, chlorophenyl,dichlorophenyl, trichlorophenyl, tetrachlorophenyl, pentachlorophenyl,fluorophenyl, bromophenyl, chloromethylphenyl, chlorodimethylphenyl,dichlorotrifluoromethylphenyl, chlorobromophenyl, chloronitrophenyl,trifluoromethylphenyl, dichlorotrifluoromethylphenyl, tolyl,dimethylphenyl, t-butylphenyl, methylnitrophenyl, methoxyphenyl,aminophenyl, diphenyl or phenylbromophenyl; and R3 methyl or t-butyl.23. A method according to claim 19 wherein the 1,2,4-triazole is in theform of salt and said salt is selected from the group consisting of thehydrohalides, the phosphates, nitrates, monofunctional and difunctionalcarboxylates, hydroxycarboxylates and 1,5-naphthalenedisulphonate.
 24. Amethod according to claim 23 wherein the salt is selected from the groupconsisting of the hydrochloride, the hydrobromide, the phosphate,nitrate, acetate, maleate succinate, fumarate, tartrate, citrate,salicylate, sorbate, lactate and 1,5-naphthalenedisulphonate.
 25. Amethod according to claim 19 wherein the 1,2,4-triazole is in the formof the hydrochloride salt.
 26. The method according to claim 19 whereinthe 1,2,4-triazole is1-((2'',4''-dichloro)-phenoxy)-1-(1'',2'',4''-trizolyl(1''))-3,3-dimethyl-butan-2-one or the or the hydrochloride salt thereof.
 27. The method accordingto claim 19 wherein the 1,2,4-triazole is of the formula:
 28. The methodaccording to claim 19 wherein the 1,2,4-triazole is of the formula: 29.The method according to claim 19 wherein the 1,2,4-triazole is of theformula:
 30. The method according to claim 19 wherein the 1,2,4-triazoleis of the formula:
 31. The method according to claim 19 wherein the1,2,4-triazole is of the formula:
 32. The method according to claim 19wherein the 1,2,4-triazole is of the formula:
 33. A method according toclaim 19 wherein the administration is oral.
 34. A method according toclaim 19 wherein the administration is by topical application.
 35. Amethod accordng to claim 19 wherein the administration is by tablet. 36.A method according to claim 35 wherein each tablet contains 200 ml ofactive agent.
 37. A method according to claim 19 wherein theantimycotically effective amount is from 300 to 250 mg/kg per day.
 38. Amethod according to claim 37 wherein the antimycotically effectiveamount is from 50 to 200 mg/kg. per day.